EP2917221A1 - Dérivés de thiophène condensés tricycliques à titre d'inhibiteurs de jak - Google Patents

Dérivés de thiophène condensés tricycliques à titre d'inhibiteurs de jak

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Publication number
EP2917221A1
EP2917221A1 EP13789679.1A EP13789679A EP2917221A1 EP 2917221 A1 EP2917221 A1 EP 2917221A1 EP 13789679 A EP13789679 A EP 13789679A EP 2917221 A1 EP2917221 A1 EP 2917221A1
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EP
European Patent Office
Prior art keywords
alkyl
independently selected
optionally substituted
pyridin
thieno
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP13789679.1A
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German (de)
English (en)
Inventor
Yun-Long Li
Wenyu Zhu
Song MEI
Joseph Glenn
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Incyte Holdings Corp
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Incyte Corp
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Application filed by Incyte Corp filed Critical Incyte Corp
Publication of EP2917221A1 publication Critical patent/EP2917221A1/fr
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    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

  • the present invention provides tricyclic fused thiophene derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.
  • JAK Janus kinase
  • Protein kinases regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens.
  • JAKs Janus kinase family
  • JAK2 Janus kinase- 1
  • JAK2 JAK3
  • TYK2 protein-tyrosine kinase 2
  • Cytokine-stimulated immune and inflammatory responses contribute to pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while a hyperactive or inappropriate immune/inflammatory response contributes to the pathology of autoimmune diseases (e.g. , asthma, systemic lupus erythematosus, thyroiditis, myocarditis), and illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000) Arthritis Res 2(1): 16-32).
  • SCID severe combined immunodeficiency
  • JAKs Deficiencies in expression of JAKs are associated with many disease states. For example, Jakl-/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998) Cell 93(3): 373-83). Jak2-/- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis.
  • the JAK/STAT pathway and in particular all four JAKs, are believed to play a role in the pathogenesis of asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract.
  • Multiple cytokines that signal through JAKs have been linked to inflammatory diseases/conditions of the upper respiratory tract, such as those affecting the nose and sinuses (e.g., rhinitis and sinusitis) whether classically allergic reactions or not.
  • the JAK/STAT pathway has also been implicated in inflammatory diseases/conditions of the eye and chronic allergic responses.
  • Activation of JAK/STAT in cancers may occur by cytokine stimulation (e.g. IL-6 or GM-
  • JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative disorders, e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM) (Levin, et al, Cancer Cell, vol. 7, 2005: 387-397).
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • JAKs may benefit patients suffering from skin immune disorders such as psoriasis, and skin sensitization.
  • skin immune disorders such as psoriasis, and skin sensitization.
  • the maintenance of psoriasis is believed to depend on a number of inflammatory cytokines in addition to various chemokines and growth factors (JCI, 1 13: 1664- 1675), many of which signal through JAKs (Adv Pharmacol. 2000;47: 1 13-74).
  • new or improved agents which inhibit kinases such as JAKs are continually needed for developing new and more effective pharmaceuticals that are aimed at augmentation or suppression of the immune and inflammatory pathways (such as immunosuppressive agents for organ transplants), as well as agents for the prevention and treatment of autoimmune diseases, diseases involving a hyperactive inflammatory response (e.g., eczema), allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune reactions (e.g., skin rash or contact dermatitis or diarrhea) caused by other therapeutics.
  • the compounds of the invention, as well as its compositions and methods described herein are directed toward these needs and other ends.
  • the present invention provides, inter alia, compounds of Formula I:
  • the present invention further provides compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating an activity of JAK1 comprising contacting JAK1 with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of treating a disease or a disorder associated with abnormal kinase expression or activity in a patient by administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides compounds of Formula I, or pharmaceutically acceptable salts thereof, as described herein for use in treatment of autoimmune diseases, cancer, myeloproliferative disorders, inflammatory diseases, a bone resorption disease, or organ transplant rejection.
  • the present invention further provides compounds of Formula I as described herein, or pharmaceutically acceptable salts thereof, for use in modulating JAKl .
  • the present invention also provides uses of compounds of Formula I as described herein, or pharmaceutically acceptable salts thereof, for the preparation of medicaments for use in methods of modulating JAKl .
  • the present invention provides, inter alia, a compound of Formula I:
  • each— is independently selected from a single bond and a double bond
  • Y is N or CR 4 ;
  • X 3 is selected from CR 3 and NR 3 ;
  • X 4 is selected from C and N; and X 5 is C; or
  • X 4 is C; and X 5 is selected from C and N;
  • R 1 is selected from H, halo, CN, NH 2 , Ci_ 3 alkyl, Ci_ 3 alkoxy, and Ci_ 3 haloalkyl;
  • R la is selected from H, halo, CN, NH 2 , Ci_ 3 alkyl, and Ci_ 3 haloalkyl;
  • R 2a is selected from CN, OH, OCH 3 , and N0 2 ;
  • Cy 4 is unsubstituted or substituted 3-10 membered saturated heterocycloalkylene having one or more nitrogen atoms or Cy 4A is unsubstituted or substituted 3-10 membered saturated
  • heterocycloalkyl ring are independently selected from N, O and S; and wherein said cycloalkyl ring and heterocycloalkyl ring are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, OH, CN, Ci_3 alkyl, d_3 alkoxy, and Q_3 haloalkyl;
  • each R e is independently selected from H, CN, OH, d_ 4 alkyl, Ci_ 4 alkoxy, N0 2 , C(0)(Ci_
  • each R al , R cl , and R dl are independently selected from H, Ci_3 alkyl, C 2 _3 alkenyl, C 2 _3 alkynyl, and Ci_ 3 haloalkyl;
  • each R bl is independently selected from Ci_ 3 alkyl, C 2 _ 3 alkenyl, C 2 _ 3 alkynyl, and Ci_ 3 haloalkyl;
  • each R el is independently selected from H, CN, OH, Ci_ 4 alkyl, and Ci_4 alkoxy;
  • R 3 is selected from Cy 4 , -Cy 4A -Cy 5 , -Cy ⁇ -Y ⁇ Cy 5 , -Cy ⁇ -Y ⁇ Cy ⁇ -Cy 6 , -Cy 4A -Cy 5A -Y 2 - Cy 6 , -Cy ⁇ -Y ⁇ Cy ⁇ -Y'-Cy 6 , or -Cy 4A -Y 3 -Cy 6 ;
  • Cy 4 is selected from C6-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl, wherein said C6-10 aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups;
  • Cy 4A is selected from C 6 _io arylene, C 3 _i 0 cycloalkylene, 5- 10 membered heteroarylene, and 3- 10 membered heterocycloalkylene, wherein said Ce-io arylene, C3_io cycloalkylene, 5- 10 membered heteroarylene, and 3- 10 membered heterocycloalkylene are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups;
  • Y 1 is Y 11 , Ci_6 alkylene, C2-6 alkenylene, C2-6 alkynylene, Q_6 alkylene-Y 11 , C2-6 alkenylene-Y 11 , C 2 - 6 alkynylene-Y 11 , Y u -Ci_ 6 alkylene, Y u -C 2 -6 alkenylene, or Y u -C 2 -6 alkynylene, wherein said alkylene, alkenylene and alkynylene groups are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, CN, OH, Ci_3 alkyl, Ci_3 alkoxy, Q_3 haloalkyl, and Q_3 haloalkoxy;
  • Cy 5 and Cy 6 are each independently selected from C6-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl, wherein said Ce-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 32 groups;
  • Cy 5A is selected from C 6 _io arylene, C 3 _i 0 cycloalkylene, 5- 10 membered heteroarylene, and 3- 10 membered heterocycloalkylene, wherein said C 6 _io arylene, C 3 _i 0 cycloalkylene, 5- 10 membered heteroarylene, and 3- 10 membered heterocycloalkylene are each optionally substituted with 1 , 2, 3, or 4 independently selected R 32 groups;
  • Y 2 is Y 21 , Ci_6 alkylene, C2-6 alkenylene, C2-6 alkynylene, Q_6 alkylene-Y 21 , C2-6 alkenylene-Y 21 , C 2 - 6 alkynylene-Y 21 , Y 21 -Ci_ 6 alkylene, Y 21 -C 2 - 6 alkenylene, or Y 21 -C 2 - 6 alkynylene, wherein said alkylene, alkenylene and alkynylene groups are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, CN, OH, Ci_3 alkyl, Ci_3 alkoxy, Q_3 haloalkyl, and Q_3 haloalkoxy;
  • Y 3 is Ci_6 alkylene-Y 31 -Ci_ 6 alkylene, Ci_ 6 alkylene-Y 31 -Ci_ 6 alkylene-Y 31 , or Y 31 -Ci_ 6 alkylene -Y 31 -Ci_6 alkylene, wherein said alkylene groups are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, CN, OH, Ci_3 alkyl, d_3 alkoxy, Ci_3 haloalkyl, and Q_3 haloalkoxy;
  • each Cy 7 is independently selected from C6-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl, wherein said C6-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are each optionally substituted with 1 , 2, 3, 4, or 5 independently selected R 33 groups;
  • each R 33 is independently selected from halo, OH, N0 2 , CN, Ci_ 3 alkyl, C 2 _ 3 alkenyl, C 2 _ 3 alkynyl, d_ 3 haloalkyl, cyano-Ci_ 3 alkyl, HO-Ci_ 3 alkyl, Ci_ 3 alkoxy-Ci_ 3 alkyl, C 3 _ 7 cycloalkyl, Ci_ 3 alkoxy, Ci_ 3 haloalkoxy, amino, Q_ 3 alkylamino, di(Ci_ 3 alkyl)amino, thio, Ci_ 3 alkylthio, Ci_ 3 alkylsulfinyl, d_ 3 alkylsulfonyl, carbamyl, Ci_ 3 alkylcarbamyl, di(Ci_ 3 alkyl)carbamyl, carboxy, Ci_ 3 alkylcarbonyl, Ci_4 alkoxycarbonyl, Ci_ 3 alkylcarbon
  • heterocycloalkyl ring are independently selected from N, O and S; and wherein said cycloalkyl ring and heterocycloalkyl ring are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, OH, CN, Q_ 3 alkyl, Q_ 3 alkoxy, and Q_ 3 haloalkyl; each R a , R c , and R are independently selected from H, Ci_ 6 alkyl, C 2 -e alkenyl, C 2 -e alkynyl, and Ci_6 haloalkyl, wherein said Q_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2,or 3 substituents independently selected from R 33 ;
  • each R b2 is independently selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Q_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 33 ;
  • each R e2 is independently selected from H, CN, OH, d_4 alkyl, and Ci_4 alkoxy;
  • each R f is independently selected from H and Ci_3 alkyl
  • R 4 is selected from H, halo, CN, NH 2 , Ci_ 3 alkyl, and Ci_ 3 haloalkyl;
  • R 5 is selected from H, halo, cyano, hydroxy, amino, (Ci_4 alkyl)amino, di(Ci_4 alkyl)amino, Ci_4 alkyl, Ci_4 haloalkyl, and Ci_4 alkoxy.
  • each— is independently selected from a single bond and a double bond
  • Y is N or CR 4 ;
  • X 3 is selected from CR 3 and NR 3 ;
  • X 4 is selected from C and N; and X 5 is C; or
  • X 4 is C; and X 5 is selected from C and N;
  • R 1 is selected from H, halo, CN, NH 2 , Ci_ 3 alkyl, Ci_ 3 alkoxy, and Q_ 3 haloalkyl;
  • R la is selected from H, halo, CN, NH 2 , Ci -3 alkyl, and Q_ 3 haloalkyl;
  • R 2a is selected from CN, OH, OCH 3 , and N0 2 ;
  • heterocycloalkyl ring are independently selected from N, O and S; and wherein said cycloalkyl ring and heterocycloalkyl ring are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, OH, CN, Ci_3 alkyl, d_3 alkoxy, and Q_3 haloalkyl;
  • each R a , R c , and R d are independently selected from H, d_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, d_6 haloalkyl, C6-io aryl, C3_io cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein said Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, Ce-io aryl, C3_io cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Q_6 alkyl, C 2 _6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, CN, N0 2 , OR al , SR al ,
  • each R b is independently selected from d_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, d_6 haloalkyl, C6-io aryl, C3_io cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered
  • each R e is independently selected from H, CN, OH, Ci_ 4 alkyl, Ci_ 4 alkoxy, N0 2 , C(0)(Ci_
  • each R al , R cl , and R dl are independently selected from H, Ci_3 alkyl, C 2 _3 alkenyl, C 2 _3 alkynyl, and Ci_3 haloalky;
  • each R bl is independently selected from Ci_ 3 alkyl, C 2 _ 3 alkenyl, C 2 _ 3 alkynyl, and Ci_ 3 haloalkyl;
  • R 3 is Cy 4 , -Cy 4A -Cy 5 ,
  • Cy 4 is selected from C6-io aryl, C3 0 cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein said Ce-io aryl, C3 0 cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, wherein said 3-10 membered heterocycloalkyl is not a saturated
  • heterocycloalkyl group having one or more nitrogen ring members having one or more nitrogen ring members
  • Cy 4A is selected from C 6 _io arylene, C 3 _i 0 cycloalkylene, 5-10 membered heteroarylene, and 3-10 membered heterocycloalkylene, wherein said Ce-io arylene, C3_io cycloalkylene, 5-10 membered heteroarylene, and 3-10 membered heterocycloalkylene are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, wherein said 3-10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members;
  • Y 1 is Y 11 , Ci_6 alkylene, C 2 _6 alkenylene, C 2 _6 alkynylene, Q_6 alkylene-Y 11 , C 2 _6 alkenylene-Y 11 , C 2 _ 6 alkynylene-Y 11 , Y u -Ci_ 6 alkylene, Y u -C 2 _ 6 alkenylene, or Y u -C 2 _ 6 alkynylene, wherein said alkylene, alkenylene and alkynylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, d_3 alkyl, Ci_3 alkoxy, Q_3 haloalkyl, and Q_3 haloalkoxy;
  • Cy 5 and Cy 6 are each independently selected from C6-io aryl, C3 0 cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein said Ce-io aryl, C340 cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 independently selected R 32 groups;
  • Cy 5A is selected from Ce-io arylene, C3 0 cycloalkylene, 5-10 membered heteroarylene, and 3-10 membered heterocycloalkylene, wherein said C 6 4o arylene, C340 cycloalkylene, 5-10 membered heteroarylene, and 3-10 membered heterocycloalkylene are each optionally substituted with 1, 2, 3, or 4 independently selected R 32 groups;
  • Y 2 is Y 21 , Ci_6 alkylene, C 2 _6 alkenylene, C 2 _6 alkynylene, Ci_6 alkylene-Y 21 , C2-6 alkenylene-Y 21 , C 2 - 6 alkynylene-Y 21 , Y 21 -Ci_ 6 alkylene, Y 21 -C 2 - 6 alkenylene, or Y 21 -C 2 - 6 alkynylene, wherein said alkylene, alkenylene and alkynylene groups are each optionally substituted with 1,
  • Y 3 is Ci_6 alkylene-Y 31 -Ci_ 6 alkylene, Ci_ 6 alkylene-Y 31 -Ci_ 6 alkylene-Y 31 , or Y 31 -Ci_ 6 alkylene -Y 31 -Ci_6 alkylene, wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, Ci_3 alkyl, d_3 alkoxy, Ci_3 haloalkyl, and Ci_3 haloalkoxy;
  • each Cy 7 is independently selected from Ce-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein said C6-io aryl, C3_io cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R 33 groups;
  • each R 33 is independently selected from halo, OH, N0 2 , CN, Ci_ 3 alkyl, C 2 _ 3 alkenyl, C 2 _ 3 alkynyl, d_ 3 haloalkyl, cyano-Ci_ 3 alkyl, HO-Ci_ 3 alkyl, Ci_ 3 alkoxy-Ci_ 3 alkyl, C 3 _ 7 cycloalkyl, Ci_ 3 alkoxy, Ci_ 3 haloalkoxy, amino, Ci_ 3 alkylamino, di(Ci_ 3 alkyl)amino, thio, Ci_ 3 alkylthio, Ci_ 3 alkylsulfinyl, Ci_ 3 alkylsulfonyl, carbamyl, Ci_ 3 alkylcarbamyl, di(Ci_ 3 alkyl)carbamyl, carboxy, Ci_ 3 alkylcarbonyl, Ci_4 alkoxycarbonyl, Ci_ 3 alkylcarbony
  • heterocycloalkyl ring are independently selected from N, O and S; and wherein said cycloalkyl ring and heterocycloalkyl ring are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, OH, CN, Ci_ 3 alkyl, Ci_ 3 alkoxy, and Q_ 3 haloalkyl;
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, and Ci_6 haloalkyl, wherein said Q_6 alkyl, C 2 _6 alkenyl, and C 2 _6 alkynyl are each optionally substituted with 1, 2,or 3 substituents independently selected from R 33 ;
  • each R b2 is independently selected from Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, and Ci_6 haloalkyl, wherein said Q_6 alkyl, C 2 _6 alkenyl, and C 2 _6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 33 ;
  • each R e2 is independently selected from H, CN, OH, d_4 alkyl, and Ci_4 alkoxy;
  • each R f is independently selected from H and Ci_ 3 alkyl
  • R 4 is selected from H, halo, CN, NH 2 , Ci_ 3 alkyl, and Q_ 3 haloalkyl;
  • R 5 is selected from H, halo, cyano, hydroxy, amino, (Ci_4 alkyl)amino, di(Ci_4 alkyl)amino, Ci_4 alkyl, Ci_4 haloalkyl, and Ci_4 alkoxy.
  • R 2 is H, Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, Ci_6 haloalkyl, Ci_6 alkoxy, Ci_6 alkyl-S-,
  • R 2 is Ci_ 6 alkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, Ci_ 6 alkoxy, S(Ci_ 6 alkyl),
  • R 2 is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R 21 groups.
  • each R 21 is independently d_3 alkyl.
  • R 2 is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R 21 groups;
  • each R 21 is independently Ci_3 alkyl.
  • R 2 is -CH 2 -OH, -CH(CH 3 )-OH, or -CH 2 -NHS0 2 CH 3 .
  • R 4 is H.
  • R 5 is H.
  • R 3 is selected from Cy 4 , -Cy 4A -Cy 5 , -Cy 4A -Cy 5A -C 6 , -Cy ⁇ -Y ⁇ Cy 5 , and -Cy 4A -Y 3 -Cy 6 .
  • Y 1 is Y 11 , Ci_6 alkylene, Ci_ 6 alkylene-Y 11 , or Y u -Ci_ 6 alkylene;
  • Y 2 is Y 21 , Ci_6 alkylene, Ci_ 6 alkylene-Y 21 , or Y 21 -Ci_ 6 alkylene;
  • Y 3 is Ci_6 alkylene-Y 31 -Ci_ 6 alkylene, Ci_ 6 alkylene-Y 31 -Ci_ 6 alkylene-Y 31 , or Y 31 -Ci_ 6 alkylene -Y 31 -Ci_6 alkylene;
  • Y 11 , Y 21 , and Y 31 are each independently selected from O and NR f .
  • R 3 is Cy 4 , -Cy 4A -Cy 5 , or -Cy ⁇ -Y ⁇ Cy 5 .
  • R 3 is -Cy 4A -Cy 5 or or -Cy ⁇ -Y ⁇ Cy 5 . In some embodiments, R 3 is Cy 4 or -Cy 4A -Cy 5 .
  • R 3 is Cy 4 .
  • R 3 is -Cy 4A -Cy 5 .
  • R 3 is -Cy 4A -Cy 5A -Cy 6 .
  • R 3 is -Cy ⁇ -Y ⁇ Cy 5 .
  • R 3 is
  • R 3 is -Cy ⁇ -Y ⁇ Cy ⁇ -Cy 6 .
  • R 3 is -Cy 4A -Cy 5A -Y 2 -Cy 6 .
  • R 3 is -Cy ⁇ -Y ⁇ Cy ⁇ -Y ⁇ Cy 6 .
  • R 3 is -Cy 4A -Y 3 -Cy 6 .
  • Y 1 is Y 11 , Ci_6 alkylene, Ci_6 alkylene-Y 11 , or Y u -Ci_6 alkylene.
  • Y is Y , Ci_ 6 alkylene, Ci_ 6 alkylene-Y , or Y -Ci_ 6 alkylene.
  • Y 3 is Ci_ 6 alkylene-Y 31 -Ci_ 6 alkylene, Ci_ 6 alkylene-Y 31 -Ci_ 6 alkylene-Y 31 , or Y 31 - ⁇ alkylene- Y 31 -dminister 6 alkylene.
  • Y 11 , Y 21 , and Y 31 are each independently selected from O and NR f .
  • Cy 4 is selected from C6-io aryl, C3_io cycloalkyl and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, provided said 3-10 membered heterocycloalkyl is not a saturated heterocycloalkyl group having one or more nitrogen ring members.
  • Cy 4 is phenyl, cyclohexyl, tetrahydro-2H-pyran ring, a piperidine ring, or a pyrrolidine ring, each which is optionally substituted with 1, 2, 3, or 4 substituents independently selected R 31 groups.
  • Cy 4 is selected from C3_io cycloalkyl and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, provided said 3- 10 membered heterocycloalkyl is not a saturated
  • heterocycloalkyl group having one or more nitrogen ring members.
  • Cy 4 is C3_io cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups.
  • Cy 4 is selected from cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups.
  • Cy 4 is selected from cyclohexyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups. In some embodiments, Cy is a tetrahydro-2H-pyran ring, which is optionally substituted with 1 or 2 independently selected R 31 groups.
  • Cy 4 is a cyclohexyl, tetrahydro-2H-pyran ring, or a piperidine ring each which is optionally substituted with 1, 2, 3, or 4 substituents independently selected R 31 groups.
  • Cy 4 is piperidin-4-yl, which is optionally substituted with 1 or 2 independently selected R 31 groups.
  • Cy 4A is selected from C3_io cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups , provided said 3-10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members.
  • Cy 4A is selected from C3_io cycloalkylene, which is optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups.
  • Cy 4A is selected from C 3 _ 7 cycloalkylene, which is optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups.
  • Cy 4A is selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups.
  • Cy 4A is selected from cyclohexylene, each of which is optionally substituted with 1 or 2 independently selected R 31 groups.
  • Cy 5 is 5- 10 membered heteroaryl, which is optionally substituted with 1 or 2 independently selected R 32 groups.
  • Cy 5 is lH-l,2,4-triazolyl, which is optionally substituted with 1 or 2 independently selected R 32 groups.
  • Cy 5 is lH-l,2,4-triazolyl.
  • Cy 5 is Ce-io aryl or 5- 10 membered heteroaryl, which are each optionally substituted with 1 or 2 independently selected R 32 groups.
  • Cy 5 is a pyridine ring, a pyrazole ring, or a triazole ring, each of which is optionally substituted with 1 or 2 independently selected R 32 groups.
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl;
  • each R b2 is independently selected from Ci_ 6 alkyl and Ci_ 6 haloalkyl.
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl, wherein said Ci_6 alkyl, and Ci_6 haloalkyl are each optionally substituted by 1, 2, or 3 CN; and each R b2 is independently selected from Ci_6 alkyl and Ci_6 haloalkyl, which are each optionally substituted by 1 , 2, or 3 CN.
  • each R 31 is independently selected from CN, OH, F, CI, Ci_4 alkyl, Ci_4 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, Ci_3 alkylcarbonyl, Ci_4 alkoxycarbonyl, amino, Ci_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Ci_4 alkyl, Ci_3 alkylcarbonyl, Ci_3 alkylamino, and di(Ci_3 alkyl)amino are each optionally substituted with 1 , 2, or 3 substituents independently selected from F, CI, CN, carbamyl, Ci_ 3 alkylcarbamyl, di(Ci_ 3 alkyl)carbamyl, Ci_ 3 alkylaminosulfonyl, Ci_ 3 alkylsulfonyl, amino, Ci_ 3 alkylamino, and di(Ci_ 3 alkyl)a
  • each R is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano-Ci_3 alkyl, HO-Ci_3 alkyl, amino, Ci_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Ci_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Ci_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl.
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl;
  • each R b2 is independently selected from Ci_ 6 alkyl and Ci_ 6 haloalkyl.
  • each R 32 is independently selected from CN, OH, F, CI, Ci_ 3 alkyl, Ci_3 haloalkyl, cyano-Ci_ 3 alkyl, HO-Ci_ 3 alkyl, amino, Ci_ 3 alkylamino, and di(Ci_ 3 alkyl)amino, wherein said Ci_ 3 alkyl and di(Ci_ 3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Ci_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl.
  • R 3 is Cy 4 or -Cy 4A -Cy 5 ;
  • Cy 4 is selected from C 6 _io aiyl > C 3 _i 0 cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein said C 6 _io ary C 3 _i 0 cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 independently selected R groups;
  • Cy 4A is selected from Ce-io arylene, C3_io cycloalkylene, 5- 10 membered heteroarylene, and 3- 10 membered heterocycloalkylene, wherein said C6-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups;
  • Cy 5 is selected from C6-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl, wherein said Ce-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 32 groups;
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl; each R b2 is independently selected from Ci_6 alkyl and Ci_6 haloalkyl;
  • R 4 is H
  • R 5 is H.
  • R 3 is Cy 4 or -Cy 4A -Cy 5 ;
  • Cy 4 is selected from C6-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl, wherein said Ce-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups;
  • Cy 4A is selected from C 6 4o arylene, C 3 4 0 cycloalkylene, 5- 10 membered heteroarylene, and 3- 10 membered heterocycloalkylene, wherein said C6-io aryl, C3_io cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups;
  • Cy 5 is selected from C6-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl, wherein said Ce-io aryl, C3 0 cycloalkyl, 5- 10 membered heteroaryl, and 3- 10 membered heterocycloalkyl are optionally substituted with 1 , 2, 3, or 4 independently selected R 32 groups;
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl; each R b2 is independently selected from Ci_6 alkyl and Ci_6 haloalkyl;
  • R 4 is H
  • R 5 is H.
  • R 3 is Cy 4 or -Cy 4A -Cy 5 ;
  • Cy 4 is selected from C3_io cycloalkyl and 3- 10 membered heterocycloalkyl, each of which are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups, provided said 3- 10 membered heterocycloalkyl is not a saturated heterocycloalkyl group having one or more nitrogen ring members;
  • Cy 4A is selected from C 3 _i 0 cycloalkylene and 3- 10 membered heterocycloalkylene, each of which are optionally substituted with 1 , 2, 3, or 4 independently selected R 31 groups, provided said 3- 10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members;
  • Cy 5 is selected from C6-io aryl, C3_io cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein said Ce-io aryl, C3_io cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 independently selected R 32 groups;
  • each R 31 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Ci_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Q_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl;
  • each R 32 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Q_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Ci_ 3 alkylaminosulfonyl, and Ci_ 3 alkylsulfonyl;
  • R 4 is H
  • R 5 is H.
  • R 2 is -CH 2 -OH, -CH(CH 3 )-OH, or -CH 2 -NHS0 2 CH 3 ;
  • R 3 is Cy 4 or -Cy 4A -Cy 5 ;
  • Cy 4 is selected from C 3 _io cycloalkyl and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, provided said 3-10 membered heterocycloalkyl is not a saturated heterocycloalkyl group having one or more nitrogen ring members;
  • Cy 4A is selected from C 3 _io cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups , provided said 3- 10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members;
  • Cy 5 is selected from 5-10 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 32 groups;
  • each R 31 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Q_3 alkyl and di(Ci_ 3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Ci_ 3 alkylaminosulfonyl, and Ci_ 3 alkylsulfonyl;
  • each R 32 is independently selected from CN, OH, F, CI, Ci_ 3 alkyl, Ci_ 3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Ci_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Q_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Q_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl;
  • R 4 is H
  • R 5 is H.
  • R 2 is -CH 2 -OH, -CH(CH 3 )-OH, or -CH 2 -NHS0 2 CH 3 ;
  • R 3 is Cy 4 ;
  • Cy 4 is selected from C3_io cycloalkyl and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, provided said 3-10 membered heterocycloalkyl is not a saturated heterocycloalkyl group having one or more nitrogen ring members;
  • each R 31 is independently selected from CN, OH, F, CI, Ci_ 3 alkyl, Ci_ 3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_ 3 alkyl, amino, Ci_ 3 alkylamino, and di(Ci_ 3 alkyl)amino, wherein said Ci_ 3 alkyl and di(Ci_ 3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Ci_ 3 alkylaminosulfonyl, and Ci_ 3 alkylsulfonyl;
  • R 4 is H
  • R 5 is H.
  • R 2 is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R 21 groups;
  • each R 21 is independently Ci_3 alkyl
  • R 3 is Cy 4 , -Cy 4A -Cy 5 , or -Cy ⁇ -Y ⁇ Cy 5 ;
  • Y 1 is Ci_ 4 alkylene or Y u -Ci_ 4 alkylene
  • Cy 4 is selected from C 6 _io aiyl > C 3 _i 0 cycloalkyl, and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 group, provided said 3- 10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members;
  • Cy 4A is selected from C3_io cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups, provided said 3- 10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members;
  • Cy 5 is Ce-io aryl or 5-10 membered heteroaryl, which are each optionally substituted with 1 or 2 independently selected R 32 groups;
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl, wherein said Ci_ 6 alkyl, and Ci_ 6 haloalkyl are each optionally substituted by 1, 2, or 3 CN; each R b2 is independently selected from Ci_ 6 alkyl and Ci_ 6 haloalkyl, which are each optionally substituted by 1 , 2, or 3 CN;
  • R 4 is H
  • R 5 is H.
  • R 2 is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R 21 groups;
  • Cy 4 is unsubstituted or substituted 3-10 membered saturated heterocycloalkylene having one or more nitrogen atoms or Cy 4A is unsubstituted or substituted 3-10 membered saturated
  • each R 21 is independently Ci_3 alkyl
  • Y 1 is Ci_ 4 alkylene, Y u -Ci 4 alkylene, or Ci_ 6 alkylene-Y 11 ;
  • Cy 4 is selected from phenyl, cycloalkyl, and 4-6 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 group; Cy 4A is selected from C3_ 7 cycloalkylene and 4-6 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups;
  • Cy 5 is phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, which are each optionally substituted with 1 or 2 independently selected R 32 groups;
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, and wherein said Ci_6 alkyl, and Q_6 haloalkyl are each optionally substituted by 1, 2, or 3 CN;
  • each R b2 is independently selected from Ci_6 alkyl and Ci_6 haloalkyl, which are each optionally substituted by 1 , 2, or 3 CN;
  • R 4 is H
  • R 5 is H.
  • R 2 is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R 21 groups;
  • each R 21 is independently Ci_3 alkyl
  • Y 1 is Ci_ 4 alkylene or Y u -Ci_ 4 alkylene
  • Cy 4 is selected from C6-io aryl, C3_io cycloalkyl, and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 group;
  • Cy 4A is selected from C3_io cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups;
  • Cy 5 is C 6 _io aryl or 5-10 membered heteroaryl, which are each optionally substituted with 1 or 2 independently selected R 32 groups;
  • each R a2 , R c2 , and R d2 are independently selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl, wherein said Ci_6 alkyl, and Q_6 haloalkyl are each optionally substituted by 1, 2, or 3 CN; each R b2 is independently selected from Ci_6 alkyl and Ci_6 haloalkyl, which are each optionally substituted by 1 , 2, or 3 CN;
  • R 4 is H
  • R 5 is H.
  • R 2 is -CH 2 -OH, -CH(CH 3 )-OH, or -CH 2 -NHS0 2 CH 3 ;
  • R is -Cy -Cy ;
  • Cy 4A is selected from C3_io cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups , provided said 3- 10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members; Cy 5 is selected from 5-10 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 32 groups;
  • each R 31 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Q_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Q_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl;
  • each R 32 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Ci_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Q_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl;
  • R 4 is H
  • R 5 is H.
  • R 2 is -CH 2 -OH, -CH(CH 3 )-OH, or -CH 2 -NHS0 2 CH 3 ;
  • R 3 is Cy 4 or -Cy 4A -Cy 5 ;
  • Cy 4 is selected from cyclohexylene and a 2H-tetrahydrofuran ring, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups;
  • Cy 4A is selected from cyclohexylene and a 2H-tetrahydrofuran ring, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R 31 groups ;
  • Cy 5 is selected from 5-10 membered heteroaryl, which is optionally substituted with 1, 2,
  • each R 31 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Q_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Q_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl;
  • each R 32 is independently selected from CN, OH, F, CI, Q_3 alkyl, Ci_3 haloalkyl, cyano- Ci_3 alkyl, HO-Ci_3 alkyl, amino, Q_3 alkylamino, and di(Ci_3 alkyl)amino, wherein said Ci_3 alkyl and di(Ci_3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, Q_3 alkylaminosulfonyl, and Ci_3 alkylsulfonyl;
  • R 4 is H
  • R 5 is H.
  • X l X 2 ⁇ 3 is -CR ⁇ CR ⁇ NR 3 -, X 4 is C, X 5 is C, and Y is CR 4 ; or
  • X 1 ! ⁇ 2 ⁇ 3 N-NR 2 -CR 3 -, X 4 is C, X 5 is C, and Y is CR 4 ; or
  • the compound is a compound of Formula Ila:
  • the compound is a compound of Formula lib
  • the compound is a compound of Formula lie:
  • the compound is a compound of Formula lid:
  • the compound is a compound of Formula He:
  • the compound is a compound of Formula Ilf:
  • the compound is a compound of Formula Ilia:
  • the compound is a compound of Formula Illb
  • la IIIc In some embodiments, la IIIc:
  • the compound is a compound of any one of Formulas IV- 1 to IV- 18:
  • the compound is a compound of any one of Formula IV- 19 to IV- :
  • the compound is a compound of Formula V:
  • the compound is a compound of Formula VI:
  • the compound is a compound of Formula VII
  • the comp a compound of Formula VIII:
  • the compound is a compound of Formula IX:
  • the compound is a compound of Formula X:
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci_6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C 5 alkyl, and Ce alkyl.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is to be understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • rings are described (e.g., "a piperidine ring”). Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • a 2H-tetrahydropyran ring may refer to a 2H-tetrahydropyran -2-yl, 2H-tetrahydropyran -3-yl, 2H-tetrahydropyran-4-yl ring, etc.
  • n-membered where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring- forming atoms is n.
  • 2H- tetrahydropyran is an example of a 6-membered heterocycloalkyl ring
  • lH- l ,2,4-triazole is an example of a 5-membered heteroaryl ring
  • pyridine is an example of a 6-membered heteroaryl ring
  • 1 ,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R.
  • an optionally multiple substituent is designated in the form:
  • substituent R can occur p number of times on the ring, and R can be a different moiety at each occurrence. It is to be understood that each R group may replace any hydrogen atom attached to a ring atom, including one or both of the (CH 2 ) n hydrogen atoms. Further, in the above example, should the variable Q be defined to include hydrogens, such as when Q is said to be CH 2 , NH, etc., any floating substituent such as R in the above example, can replace a hydrogen of the Q variable as well as a hydrogen in any other non-variable component of the ring.
  • substituted means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.
  • C n _ m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbon atoms.
  • the alkyl group contains 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, «-pentyl, 2-methyl- 1 - butyl, 3-pentyl, «-hexyl, 1 ,2,2-trimethylpropyl, and the like.
  • alkylene refers to a divalent alkyl linking group, which can be branched or straight-chain, where the two substituents may be attached any position of the alkylene linking group.
  • alkylene groups include, but are not limited to, ethan- l,2-diyl, propan-l,3-diyl, propan-l,2-diyl, butan- 1,4- diyl, butan- l,3-diyl, butan- 1 ,2-diyl, 2-methyl-propan-l,3-diyl, and the like.
  • C n _ m alkenyl refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, «-propenyl, isopropenyl, «-butenyl, sec-butenyl, and the like.
  • C n _ m alkynyl refers to an alkyl group having one or more triple carbon- carbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn- l-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkenylene employed alone or in combination with other terms, refers to a divalent alkenyl linking group, which can be branched or straight-chain, where the two substituents may be attached any position of the alkenylene linking group.
  • alkynylene employed alone or in combination with other terms, refers to a divalent alkynyl linking group, which can be branched or straight-chain, where the two substituents may be attached any position of the alkynylene linking group.
  • Ci_3 alkoxy employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has 1 to 3 carbons.
  • Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).
  • amino refers to a group of formula -NH 2 .
  • Ci_3 alkylamino refers to a group of formula -NH(alkyl), wherein the alkyl group 1 to 3 carbon atoms.
  • di(Ci_3-alkyl)amino refers to a group of formula -N(alkyl) 2 , wherein the two alkyl groups each has, independently, 1 to 3 carbon atoms.
  • Ci_4 alkoxycarbonyl refers to a group of formula -C(0)0- alkyl, wherein the alkyl group has 1 to 4 carbon atoms.
  • Ci_ 3 alkylcarbonyl refers to a group of formula -C(0)-alkyl, wherein the alkyl group has 1 to 3 carbon atoms.
  • carboxy refers to a group of formula -C(0)OH.
  • thio refers to a group of formula -SH.
  • Ci_ 3 alkylthio refers to a group of formula -S-(Ci_ 3 alkyl).
  • Ci_ 3 alkylsulfinyl refers to a group of formula -S(0)-alkyl, wherein the alkyl group has 1 to 3 carbon atoms.
  • Ci_ 3 alkylsulfonyl refers to a group of formula -S(0) 2 -alkyl, wherein the alkyl group has 1 to 3 carbon atoms.
  • Ci_ 3 alkylcarbonyloxy refers to a group of formula -OC(O)- alkyl, wherein the alkyl group has 1 to 3 carbon atoms.
  • Ci_3 alkylcarbonylamino refers to a group of
  • aminocarbonylamino refers to a group of formula - NHC(0)NH 2 .
  • Ci_3 alkylaminocarbonylamino refers to a group of formula - NHC(0)NH(alkyl), wherein said alkyl has 1 to 3 carbon atoms.
  • di(Ci_3 alkylaminocarbonylamino refers to a group of formula -NHC(0)N(alkyl) 2 , wherein each alkyl independently has 1 to 3 carbon atoms.
  • carboxylate refers to a group of formula -C(0)-NH 2 .
  • Ci_ 3 alkylcarbamyl refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has 1 to 3 carbon atoms.
  • di(Ci_3-alkyl)carbamyl refers to a group of formula - C(0)N(alkyl) 2 , wherein the two alkyl groups each has, independently, 1 to 3 carbon atoms.
  • Ci_3 alkylsulfonylamino refers to a group of formula - NHS(0) 2 -alkyl, wherein said alkyl has 1 to 3 carbon atoms.
  • aminosulfonyl refers to a group of formula -S(0) 2 NH 2 .
  • Ci_3 alkylaminosulfonyl refers to a group of formula - S(0) 2 NH(alkyl), wherein said alkyl has 1 to 3 carbon atoms.
  • di(Ci_3 alkyl)aminosulfonyl refers to a group of formula - S(0) 2 N(alkyl) 2 , wherein each alkyl independently has 1 to 3 carbon atoms.
  • aminosulfonylamino refers to a group of formula -
  • Ci_3 alkylaminosulfonylamino refers to a group of formula - NHS(0) 2 NH(alkyl), wherein said alkyl has 1 to 3 carbon atoms.
  • di(Ci_ 3 alkylaminosulfonylamino refers to a group of formula - NHS(0) 2 N(alkyl) 2 , wherein each alkyl independently has 1 to 3 carbon atoms.
  • HO-C n _ m -alkyl refers to a group of formula -alkylene-OH, wherein said alkylene group has n to m carbon atoms. In some embodiments, the alkylene group has 1 to 3 carbon atoms.
  • C 0 _ p alkoxy-C n _ m -alkyl refers to a group of formula -alkylene- O-alkyl, wherein said alkylene group has n to m carbon atoms and said alkyl group has o to p carbon atoms.
  • the alkyl and alkylene groups each independently have 1 to 3 carbon atoms.
  • carbonyl employed alone or in combination with other terms, refers to a -C(O)- group.
  • halo or halogen, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo.
  • C n _ m haloalkyl refers to an C n _ m alkyl group having up to ⁇ 2(n to m)+l ⁇ halogen atoms which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CC1 3 , CHC1 2 , C 2 C1 5 , and the like.
  • the haloalkyl group is a fluoroalkyl group.
  • C n _ m haloalkoxy refers to a group of formula -O-haloalkyl having n to m carbon atoms.
  • An example haloalkoxy group is OCF 3 .
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • cyano-C n _ m alkyl refers to a C n _ m alkyl substituted by a cyano group.
  • the alkyl group has 1 to 3 carbon atoms.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon moiety, which may optionally contain one or more alkenylene groups as part of the ring structure.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, spirocyclic, or bridged rings) ring systems.
  • moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • cycloalkyl is a 3- 10 membered cycloalkyl, which is monocyclic or bicyclic. In some embodiments, cycloalkyl is a 3-6 or 3-7 monocyclic cycloalkyl.
  • Examplary cycloalkyl groups include 1,2,3,4-tetrahydro-naphthalene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • aryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1 -naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like.
  • aryl is Ce-io aryl- I n some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen.
  • heteroaryl is a 5-10 membered heteroaryl, which is monocyclic or bicyclic, comprising 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heteroaryl is a 5-6 membered heteroaryl, which is monocyclic or bicyclic, comprising 1 to 5 carbon atoms and 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.
  • heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different.
  • Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l ,2-b]thiazole, purine, or the like.
  • a five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1 ,2,3-triazolyl, tetrazolyl, 1 ,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1 ,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-triazolyl, 1 ,3,4-triazolyl, 1 ,3,4-thiadiazolyl, and 1 ,3,4-o
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heteroarylalkyl refers to a group of formula -alkylene- heteroaryl.
  • heteroarylalkyl is Ci_ci heteroaryl-Ci_3 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl refers to non-aromatic ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, spirocyclic, or bridged rings) ring systems.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1 ,2,3,4-tetrahydro-quinoline and the like.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • heterocycloalkyl is 5- 10 membered heterocycloalkyl, which is monocyclic or bicyclic, comprising 2 to 9 carbon atoms and 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.
  • heterocycloalkyl groups include 1,2,3,4- tetrahydro-quinoline, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, pyran, and a 2-oxo-l,3-oxazolidine ring.
  • heterocycloalkylalkyl refers to a group of formula -alkylene- heterocycloalkyl.
  • heterocycloalkylalkyl is C2- 9 heterocycloalkyl-Ci_3 alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt- forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and
  • L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1 ,2- diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1 ,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • 1 , 2, or 3 CH 2 groups in the azetidine ring of Formula I are replaced by a CHD or CD 2 group.
  • 1, 2, or 3 CH 2 or CH groups in the piperidine ring of Formula I are replaced by a CHD, CD 2 or CD group, respectively.
  • 1 , 2, 3, 4, or 5 CH 2 or CH groups in the piperidine ring of Formula I are replaced by a CHD, CD 2 or CD group, respectively.
  • compound as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • ACN acetonitrile
  • Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., l H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., l H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • Coupling of compounds 3 with an appropriate R 3 -NH 2 in the presence of a suitable base such as diisopropylethylamine affords compounds 4.
  • Reduction of nitro compounds 4 using catalytic hydrogenation conditions with catalyst such as palladium or nickel or using iron or other suitable reducing conditions yields the corresponding diamines 5.
  • Condensation of compounds 5 with an appropriate amide (activated with triethyloxonium tetrafluoroborate) generates the desired compounds 6.
  • the diamine can also react with an appropriate acid R 2 C0 2 H under coupling conditions to give an amide intermediate which subsequently can be transformed compounds 6 via an intermolecular condensation.
  • the R 2 and R 3 can be further modified to desired groups. Alternatively, the R 3 can be further transformed to groups disclosed in the invention via modification on compounds 4 and 5.
  • Reaction of the iodo compounds 8 with an appropriate alkyne compound catalyzed by a suitable palladium and copper catalyst such as bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide affords compounds 9.
  • a suitable palladium and copper catalyst such as bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide
  • Condensation of 9 with R 3 -NH 2 in the presence of suitable coupling conditions such as palladium acetate, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) and cesium carbonate in toluene generates an amine coupling intermediate which cyclizes in situ with alkyne to furnish compounds of formula 10.
  • substitution R 2 can be introduced by halogenation, nitration or nucleophilic addition of the pyrole ring. Further modifications of R 1 , R 2 , R 3 , R 4 , and R 5 can be achieved in each step using methods known to one skilled in the art.
  • Reaction 13 with R 3 NH 2 under coupling conditions such as palladium acetate, (9,9-dimethyl-9H-xanthene- 4,5-diyl)bis(diphenylphosphine) and cesium carbonate in toluene can generate compounds 14.
  • Deprotection of 14 with boron tribromide gives compounds 15.
  • Treatment of 15 with triphosgene or carbonyl diimidazole then provides compounds of formula 16.
  • the deprotection of 21 to 22 can be accomplished using conditions such as trifluoroacetic acid in dichloromethane or HCl in dioxane.
  • Cyclization of 22 to compounds 23 can be accomplished by methods known to one skilled in the art, for example treatment with trifluoroacetic anhydride and trifluoroacetic acid mixture.
  • Further functionalization of R 2 , R 3 , R 4 , R 5 can be performed, if desired, using reactions know to one skilled in the art (for example, Larock, R. C. Comprehensive Organic Transformation).
  • Tribromopyrazoles 28 can be protected with a suitable protective group such as SEM to give corresponding compounds 29. Lithium-halogen exchange of 29 with butyl lithium then quenched with a suitable alkylation reagent (for example R 2 -halo) or electrophile (for example an aldehyde) provides compounds 30. Reaction of 30 with a lithium reagent such as butyl lithium followed by aqueous work up affords monobromo-pyrazoles 31.
  • a suitable alkylation reagent for example R 2 -halo
  • electrophile for example an aldehyde
  • Suzuki reaction of 31 with borates 27 can give coupling compounds 32.
  • Bromination of 32 can yield compounds 33, which can be reduced with iron to provide amines 34.
  • Deprotection of SEM can be achieved using methods known to one skilled in the art, such as reacting with trifluoroacetic acid followed by treatment with ammonium hydroxide. Condensation of 35 with ortho esters then generates tricyclic compounds 36. The later can be subjected to coupling conditions such as Suzuki coupling conditions to provide compounds of formula 37. Further modifications of substitutions, if desired, may be performed by methods known by one skilled in the art.
  • hydrazides 40 can be cyclized to compounds of formula 41 by reacting with POCI 3 or with thionyl chloride in the presence of a suitable base (for example triethylamine).
  • the coupling of amines 43 with acids R 3 C0 2 H can be achieved under standard amide coupling conditions such as HATU/diisopropylethylamine.
  • Cyclization of amides 44 to the tricylic compounds of formula 45 can be accomplished by conversion to the corresponding thioamide (by reacting with Lawesson's reagent, for example) followed by treatment with an activating agent (such as a mercury salt, a silver salt or a copper salt).
  • Ketones 49 can then be transformed to hydrazones 50 through reaction with hydrazine.
  • Cyclization of hydrazones 50 to tricyclic compounds 51 can be achieved via an intramolecular Buchwald-Hartwig cyclization.
  • Compounds 51 can be converted to compounds of formula 52 by reacting of 51 with an alkylating reagent such as R ⁇ halogen or R ⁇ OMs/R ⁇ OTs in the presence of a base such as DBU.
  • compounds of formula 53 can be prepared by treating 51 with an alkylating reagent R 2 - leaving group (leaving group is halo, OTs, OMs, OTf, etc.) in the presence of a suitable base such as sodium hydride.
  • R 2 - leaving group leaving group is halo, OTs, OMs, OTf, etc.
  • JAK inhibitors are JAK inhibitors, and the majority of the compounds of the invention, are JAK1 selective inhibitors.
  • a JAK1 selective inhibitor is a compound that inhibits JAK1 activity preferentially over other Janus kinases.
  • the compounds of the invention preferentially inhibit JAK1 over one or more of JAK2, JAK3, and TYK2.
  • the compounds inhibit JAK1 preferentially over JAK2 (e.g., have a JAK1/JAK2 IC 5 o ratio >1).
  • the compounds are about 10-fold more selective for JAK1 over JAK2.
  • the compounds are about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 over JAK2 as calculated by measuring IC 50 at 1 mM ATP (e.g., see Example A).
  • JAK1 plays a central role in a number of cytokine and growth factor signaling pathways that, when dysregulated, can result in or contribute to disease states. For example, IL-6 levels are elevated in rheumatoid arthritis, a disease in which it has been suggested to have detrimental effects (Fonesca, J.E. et al., Autoimmunity Reviews, 8:538-42, 2009). Because IL-6 signals, at least in part, through JAK1 , antagonizing IL-6 directly or indirectly through JAK1 inhibition is expected to provide clinical benefit (Guschin, D., N., et al Embo J 14: 1421 , 1995; Smolen, J. S., et al. Lancet 371 :987, 2008). Moreover, in some cancers JAK1 is mutated resulting in constitutive undesirable tumor cell growth and survival (Mullighan CG, Proc Natl Acad Sci U S
  • JAKl erythropoietin
  • Tpo thrombopoietin
  • Epo is a key growth factor for red blood cells production; hence a paucity of Epo-dependent signaling can result in reduced numbers of red blood cells and anemia (Kaushansky K, NEJM 354:2034-45, 2006).
  • Tpo another example of a JAK2-dependent growth factor, plays a central role in controlling the proliferation and maturation of megakaryocytes - the cells from which platelets are produced (Kaushansky K, NEJM 354:2034-45, 2006). As such, reduced Tpo signaling would decrease megakaryocyte numbers (megakaryocytopenia) and lower circulating platelet counts (thrombocytopenia). This can result in undesirable and/or uncontrollable bleeding.
  • JAK3 and Tyk2 may also be desirable as humans lacking functional version of these kinases have been shown to suffer from numerous maladies such as severe-combined immunodeficiency or hyperimmunoglobulin E syndrome (Minegishi, Y, et al. Immunity 25:745-55, 2006; Macchi P, et al. Nature. 377:65-8, 1995). Therefore a JAKl inhibitor with reduced affinity for other JAKs would have significant advantages over a less-selective inhibitor with respect to reduced side effects involving immune suppression, anemia and thrombocytopenia.
  • a JAK-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including overexpression and/or abnormal activity levels.
  • a JAK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity.
  • JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease).
  • organ transplant rejection e.g., allograft rejection and graft versus host disease.
  • JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, autoimmune thyroid disorders, chronic obstructive pulmonary disease (COPD), and the like.
  • the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).
  • JAK-associated diseases include allergic conditions such as asthma, food allergies, eszematous dermatitis, contact dermatitis, atopic dermatitis (atropic eczema), and rhinitis.
  • JAK-associated diseases include viral diseases such as Epstein Ban- Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1 , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).
  • EBV Epstein Ban- Virus
  • Hepatitis B Hepatitis C
  • HIV HTLV 1
  • VZV Varicella-Zoster Virus
  • HPV Human Papilloma Virus
  • JAK-associated disease examples include diseases associated with cartilage turnover, for example, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome, costal athropathy, osteoarthritis deformans endemica, Mseleni disease, Handigodu disease, degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis.
  • diseases associated with cartilage turnover for example, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome, costal athropathy, osteoarthritis deformans endemica, Mseleni disease, Handigodu disease, degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis.
  • JAK-associated disease include congenital cartilage malformations, including hereditary chrondrolysis, chrondrodysplasias, and pseudochrondrodysplasias (e.g., microtia, enotia, and metaphyseal chrondrodysplasia).
  • congenital cartilage malformations including hereditary chrondrolysis, chrondrodysplasias, and pseudochrondrodysplasias (e.g., microtia, enotia, and metaphyseal chrondrodysplasia).
  • JAK-associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
  • skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
  • certain substances including some pharmaceuticals when topically applied can cause skin sensitization.
  • co-administration or sequential administration of at least one JAK inhibitor of the invention together with the agent causing unwanted sensitization can be helpful in treating such unwanted sensitization or dermatitis.
  • the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.
  • the JAK-associated disease is cancer including those characterized by solid tumors (e.g. , prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g.
  • lymphoma leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma
  • leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma
  • skin cancer such as cutaneous T- cell lymphoma (CTCL) and cutaneous B-cell lymphoma.
  • CTCLs include Sezary syndrome and mycosis fungoides.
  • the JAK inhibitors described herein, or in combination with other JAK inhibitors, such as those reported in U.S. Ser. No. 1 1/637,545, which is incorporated herein by reference in its entirety, can be used to treat inflammation-associated cancers.
  • the cancer is associated with inflammatory bowel disease.
  • the inflammatory bowel disease is ulcerative colitis.
  • the inflammatory bowel disease is Crohn's disease.
  • the inflammation-associated cancer is colitis-associated cancer.
  • the inflammation-associated cancer is colon cancer or colorectal cancer.
  • the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), adenocarcinoma, small intestine cancer, or rectal cancer.
  • JAK-associated diseases can further include those characterized by expression of: JAK2 mutants such as those having at least one mutation in the pseudo-kinase domain (e.g. ,
  • JAK2V617F JAK2 mutants having at least one mutation outside of the pseudo-kinase domain; JAK1 mutants; JAK3 mutants; erythropoietin receptor (EPOR) mutants; or deregulated expression of CRLF2.
  • JAK-associated diseases can further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MMM myelofibrosis with myeloid metaplasia
  • PMF primary myelofibrosis
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • the myeloproliferative disorder is myelofibrosis (e.g., primary myelofibrosis (PMF) or post polycythemia vera/essential thrombocythemia myelofibrosis (Post-PV/ET MF)).
  • PMF primary myelofibrosis
  • Post-PV/ET MF post polycythemia vera/essential thrombocythemia myelofibrosis
  • myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF).
  • the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF).
  • JAK-associated disease further include myelodysplastic syndrome (MDS).
  • MDS myelodysplastic syndrome
  • the present invention further provides methods of treating psoriasis or other skin disorders by administration of a topical formulation containing a compound of the invention.
  • JAK inhibitors described herein can be used to treat pulmonary arterial hypertension.
  • the present invention further provides a method of treating dermatological side effects of other pharmaceuticals by administration of the compound of the invention.
  • numerous pharmaceutical agents result in unwanted allergic reactions which can manifest as acneiform rash or related dermatitis.
  • Example pharmaceutical agents that have such undesirable side effects include anti-cancer drugs such as gefitinib, cetuximab, erlotinib, and the like.
  • the compounds of the invention can be administered systemically or topically (e.g., localized to the vicinity of the dermatitis) in combination with (e.g., simultaneously or sequentially) the pharmaceutical agent having the undesirable dermatological side effect.
  • compositions of the invention include topical formulations containing the compound of the invention and a further pharmaceutical agent which can cause dermatitis, skin disorders, or related side effects.
  • JAK-associated diseases include inflammation and inflammatory diseases.
  • Example inflammatory diseases include sarcoidosis, inflammatory diseases of the eye (e.g., crizis, uveitis, scleritis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g. , the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases.
  • the inflammation disease of the eye is blepharitis.
  • the JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest.
  • the JAK inhibitors described herein can further be used to treat endotoxin-driven disease state (e.g., complications after bypass surgery or chronic endotoxin states contributing to chronic cardiac failure).
  • the JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer.
  • the JAK inhibitors described herein can further be used to treat restenosis, sclerodermitis, or fibrosis.
  • the JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or astrogliosis such as, for example, diabetic retinopathy, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Chem. 2004, 279(19): 19936-47. Epub 2004 Mar 2, both of which are incorporated herein by reference in their entirety.
  • the JAK inhibitors described herein can be used to treat Alzheimer's disease.
  • the JAK inhibitors described herein can further be used to treat other inflammatory diseases such as systemic inflammatory response syndrome (SIRS) and septic shock.
  • SIRS systemic inflammatory response syndrome
  • the JAK inhibitors described herein can further be used to treat gout and increased prostate size due to, e.g., benign prostatic hypertrophy or benign prostatic hyperplasia.
  • JAK-associated diseases include bone resorption diseases such as osteoporosis, osteoarthritis. Bone resorption can also be associated with other conditions such as hormonal imbalance and/or hormonal therapy, autoimmune disease (e.g. osseous sarcoidosis), or cancer (e.g. myeloma).
  • the reduction of the bone resorption due to the JAK inhibitors can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
  • JAK inhibitors described herein can further be used to treat a dry eye disorder.
  • dry eye disorder is intended to encompass the disease states summarized in a recent official report of the Dry Eye Workshop (DEWS), which defined dry eye as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolality of the tear film and inflammation of the ocular surface.” Lemp, "The Definition and Classification of Dry Eye Disease: Report of the Definition and
  • the dry eye disorder is selected from aqueous tear-deficient dry eye (ADDE) or evaporative dry eye disorder, or appropriate combinations thereof.
  • the dry eye disorder is Sjogren syndrome dry eye (SSDE).
  • the dry eye disorder is non-Sjogren syndrome dry eye (NSSDE).
  • the present invention provides a method of treating conjunctivitis, uveitis (including chronic uveitis), chorioditis, retinitis, cyclitis, sclieritis, episcleritis, or ulceris; treating inflammation or pain related to corneal transplant, LASIK (laser assisted in situ keratomileusis), photorefractive keratectomy, or LASEK (laser assisted sub-epithelial keratomileusis); inhibiting loss of visual acuity related to corneal transplant, LASIK,
  • photorefractive keratectomy, or LASEK or inhibiting transplant rejection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention can be used to treat respiratory dysfunction or failure associated wth viral infection, such as influenza and SARS.
  • the present invention provides a compound of Formula I, pharmaceutically acceptable salt thereof, as described in any of the embodiments herein, for use in a method of treating any of the diseases or disorders described herein.
  • the present invention provides the use of a compound of Formula I as described in any of the embodiments herein, for the preparation of a medicament for use in a method of treating any of the diseases or disorders described herein.
  • the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of modulating JAK1. In some embodiments, the present invention also provides use of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in a method of modulating JAK1.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a JAK with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a JAK, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the JAK.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. In some embodiments, the therapeutically effective amount is about 5 mg to about 1000 mg, or about 10 mg to about 500 mg.
  • the term "treating" or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of
  • One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006/056399, which is incorporated herein by reference in its entirety, or other agents can be used in combination with the compounds described herein for treatment of JAK-associated diseases, disorders or conditions.
  • the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • Example chemotherapeutics include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin,
  • cyclophosphamide vincristine, etoposide, carmustine, and the like.
  • Example steroids include coriticosteroids such as dexamethasone or prednisone.
  • Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491, all of which are incorporated herein by reference in their entirety.
  • Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120, all of which are incorporated herein by reference in their entirety.
  • Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444, both of which are incorporated herein by reference in their entirety.
  • Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO
  • one or more of the compounds of the invention can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.
  • a suitable chemotherapeutical agent can be selected from antimetabolite agents, topoisomerase 1 inhibitors, platinum analogs, taxanes, anthracyclines, and EGFR inhibitors, and combinations thereof.
  • antimetabolite agents include capecitabine, gemcitabine, and fluorouracil (5-FU).
  • taxanes include paclitaxel, Abraxane® (paclitaxel protein-bound particles for injectable suspension), and Taxotere® (docetaxel).
  • platinum analogs include oxaliplatin, cisplatin, and carboplatin.
  • topoisomerase 1 inhibitors include irinotecan and topotecan.
  • anthracyclines include doxorubicin or liposomal formulations of doxorubicin.
  • the chemotherapeutic is FOLFIRINOX (5-FU, lecovorin, irinotecan and oxaliplatin).
  • the chemotherapeutic agent is gemcitabine and Abraxane® (paclitaxel protein-bound particles for injectable suspension).
  • one or more JAK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects.
  • additional pharmaceutical agents used in the treatment of multiple myeloma can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade
  • Additional agents used in the treatment of multiple myeloma include Bcr- Abl, Flt-3, RAF and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the present invention with an additional agent.
  • agents such as dexamethasone may be reversible upon treatment with a JAK inhibitor of the present invention.
  • the agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor where the dexamethasone is administered intermittently as opposed to continuously.
  • combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant.
  • the additional therapeutic agent is fluocinolone acetonide (Retisert®), or rimexolone (AL-2178, Vexol, Alcon).
  • the additional therapeutic agent is cyclosporine (Restasis®).
  • the additional therapeutic agent is a corticosteroid.
  • the corticosteroid is triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
  • the additional therapeutic agent is selected from DehydrexTM (Holies Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARGIOI(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrinTM
  • the additional therapeutic agent is an anti- angiogenic agent, cholinergic agonist, TRP- 1 receptor modulator, a calcium channel blocker, a mucin secretagogue, MUC1 stimulant, a calcineurin inhibitor, a corticosteroid, a P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another JAK inhibitor, Bcr-Abl kinase inhibitor, Flt-3 kinase inhibitor, RAF kinase inhibitor, and FAK kinase inhibitor such as, for example, those described in WO 2006/056399, which is incorporated herein by reference in its entirety.
  • the additional therapeutic agent is a tetracycline derivative (e.g., minocycline or doxycline).
  • the additional therapeutic agent binds to FKBP12.
  • the additional therapeutic agent is an alkylating agent or DNA cross-linking agent; an anti-metabolite/demethylating agent (e.g., 5-flurouracil, capecitabine or azacitidine); an anti-hormone therapy (e.g., hormone receptor antagonists, SERMs, or aromotase inhibitor); a mitotic inhibitor (e.g. vincristine or paclitaxel); an topoisomerase (I or II) inhibitor (e.g. mitoxantrone and irinotecan); an apoptotic inducers (e.g. ABT-737); a nucleic acid therapy (e.g.
  • an anti-metabolite/demethylating agent e.g., 5-flurouracil, capecitabine or azacitidine
  • an anti-hormone therapy e.g., hormone receptor antagonists, SERMs, or aromotase inhibitor
  • a mitotic inhibitor e.g. vincristine or paclitaxel
  • RNAi nuclear receptor ligands
  • nuclear receptor ligands e.g., agonists and/or antagonists: all-trans retinoic acid or bexarotene
  • epigenetic targeting agents such as histone deacetylase inhibitors (e.g. vorinostat), hypomethylating agents (e.g. decitabine); regulators of protein stability such as Hsp90 inhibitors, ubiquitin and/or ubiquitin like conjugating or deconjugating molecules; or an EGFR inhibitor (erlotinib).
  • the additional therapeutic agent(s) are demulcent eye drops (also known as "artificial tears"), which include, but are not limited to, compositions containing polyvinylalcohol, hydroxypropyl methylcellulose, glycerin, polyethylene glycol (e.g. PEG400), or carboxymethyl cellulose. Artificial tears can help in the treatment of dry eye by compensating for reduced moistening and lubricating capacity of the tear film.
  • the additional therapeutic agent is a mucolytic drug, such as N-acetyl-cysteine, which can interact with the mucoproteins and, therefore, to decrease the viscosity of the tear film.
  • the additional therapeutic agent includes an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal antiinflammatories, and anti-allergic agents.
  • suitable medicaments include
  • aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin;
  • chloramphenicol neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives ("rifampins"); cycloserine; beta-lactams; cephalosporins;
  • amphotericins fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic.
  • compositions When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the pharmaceutical composition comprises silicified
  • microcrystalline cellulose and at least one compound described herein, or a
  • the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.
  • the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide.
  • the composition further comprises magnesium stearate or silicon dioxide.
  • the microcrystalline cellulose is Avicel PHI 02TM.
  • the lactose monohydrate is Fast-flo 316TM.
  • the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M PremierTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g.,
  • the polyethylene oxide is polyethylene oxide WSR 1 105 (e.g., Polyox WSR 1105TM).
  • a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compositions of the invention contain from about 5 mg to about 50 mg of the active ingredient.
  • the active ingredient contains from about 5 mg to about 50 mg.
  • One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.
  • the compositions of the invention contain from about 50 mg to about 500 mg of the active ingredient.
  • the active ingredient contains from about 50 mg to about 500 mg of the active ingredient.
  • One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.
  • the compositions of the invention contain from about 500 mg to about 1,000 mg of the active ingredient.
  • the active ingredient contains from about 500 mg to about 1,000 mg of the active ingredient.
  • this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers. In some embodiments,
  • ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g. glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like.
  • topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention.
  • the topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 1 1, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • the compound, or pharmaceutically acceptable salt thereof is administered as an ophthalmic composition.
  • the methods comprise administration of the compound, or pharmaceutically acceptable salt thereof, and an ophthalmically acceptable carrier.
  • the ophthalmic composition is a liquid composition, semi-solid composition, insert, film, microparticles or nanoparticles.
  • the ophthalmic composition is a liquid composition. In some embodiments, the ophthalmic composition is a semi-solid composition. In some embodiments, the ophthalmic composition is a topical composition. The topical compositions include, but are not limited to liquid and semi-solid compositions. In some embodiments, the ophthalmic composition is a topical composition. In some embodiments, the topical composition comprises aqueous solution, an aqueous suspension, an ointment or a gel. In some embodiments, the ophthalmic composition is topically applied to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac. In some embodiments, the ophthalmic composition is sterilized.
  • the sterilization can be accomplished by known techniques like sterilizing filtration of the solution or by heating of the solution in the ampoule ready for use.
  • the ophthalmic compositions of the invention can further contain pharmaceutical excipients suitable for the preparation of ophthalmic formulations. Examples of such excipients are preserving agents, buffering agents, chelating agents, antioxidant agents and salts for regulating the osmotic pressure.
  • the term "ophthalmically acceptable carrier” refers to any material that can contain and release the compound, or pharmaceutically acceptable salt thereof, and that is compatible with the eye.
  • the ophthalmically acceptable carrier is water or an aqueous solution or suspension, but also includes oils such as those used to make ointments and polymer matrices such as used in ocular inserts.
  • the composition may be an aqueous suspension comprising the compound, or pharmaceutically acceptable salt thereof.
  • Liquid ophthalmic compositions, including both ointments and suspensions may have a viscosity that is suited for the selected route of administration.
  • the ophthalmic composition has a viscosity in the range of from about 1,000 to about 30,000 centipoise.
  • the ophthalmic compositions may further comprise one or more of surfactants, adjuvants, buffers, antioxidants, tonicity adjusters, preservatives (e.g., EDTA, BAK (benzalkonium chloride), sodium chlorite, sodium perborate, polyquaterium- 1), thickeners or viscosity modifiers (e.g., carboxymethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol hydroxymethyl cellulose, hydroxpropyl-guar, hyaluronic acid, and hydroxypropyl cellulose) and the like.
  • Additives in the formulation may include, but are not limited to, sodium chloride, sodium bicarbonate, sorbic acid, methyl paraben, propyl paraben, chlorhexidine, castor oil, and sodium per
  • Aqueous ophthalmic compositions generally do not contain physiologically or ophthalmically harmful constituents.
  • purified or deionized water is used in the composition.
  • the pH may be adjusted by adding any
  • physiologically and ophthalmically acceptable pH adjusting acids, bases or buffers to within the range of about 5.0 to 8.5.
  • Ophthalmically acceptable examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
  • bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, trishydroxymethylamino-methane, and the like.
  • Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
  • the methods involve forming or supplying a depot of the therapeutic agent in contact with the external surface of the eye.
  • a depot refers to a source of therapeutic agent that is not rapidly removed by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of therapeutic agent to be present in the fluid on the external surface of the eye by a single application.
  • absorption and penetration may be dependent on both the dissolved drug concentration and the contact duration of the external tissue with the drug containing fluid. As the drug is removed by clearance of the ocular fluid and/or absorption into the eye tissue, more drug is provided, e.g. dissolved, into the replenished ocular fluid from the depot.
  • the use of a depot may more easily facilitate loading of the ocular tissue for more insoluble therapeutic agents.
  • the depot can remain for up to eight hours or more.
  • the ophthalmic depot forms includes, but is not limited to, aqueous polymeric suspensions, ointments, and solid inserts.
  • the ophthalmic composition is an ointment or gel.
  • the ophthalmic composition is an oil-based delivery vehicle.
  • the composition comprises a petroleum or lanolin base to which is added the active ingredient, usually as 0.1 to 2%, and excipients. Common bases may include, but are not limited to, mineral oil, petrolatum and combinations thereof.
  • the ointment is applied as a ribbon onto the lower eyelid.
  • the ophthalmic composition is an ophthalmic insert.
  • the ophthalmic insert is biologically inert, soft, bio-erodible, viscoelastic, stable to sterilization after exposure to therapeutic agents, resistant to infections from air borne bacteria, bio- erodible, biocompatible, and/or viscoelastic.
  • the insert comprises an ophthalmically acceptable matrix, e.g., a polymer matrix.
  • the matrix is typically a polymer and the therapeutic agent is generally dispersed therein or bonded to the polymer matrix.
  • the therapeutic agent may be slowly released from the matrix through dissolution or hydrolysis of the covalent bond.
  • the polymer is bioerodible (soluble) and the dissolution rate thereof can control the release rate of the therapeutic agent dispersed therein.
  • the polymer matrix is a biodegradable polymer that breaks down such as by hydrolysis to thereby release the therapeutic agent bonded thereto or dispersed therein.
  • the matrix and therapeutic agent can be surrounded with an additional polymeric coating to further control release.
  • the insert comprises a biodegradable polymer such as polycaprolactone (PCL), an ethylene/vinyl acetate copolymer (EVA), polyalkyl cyanoacrylate, polyurethane, a nylon, or poly (dl-lactide-co-glycolide) (PLGA), or a copolymer of any of these.
  • the therapeutic agent is dispersed into the matrix material or dispersed amongst the monomer composition used to make the matrix material prior to polymerization.
  • the amount of therapeutic agent is from about 0.1 to about 50%, or from about 2 to about 20%.
  • the biodegradable or bioerodible polymer matrix is used so that the spent insert does not have to be removed. As the biodegradable or bioerodible polymer is degraded or dissolved, the therapeutic agent is released.
  • the ophthalmic insert comprises a polymer, including, but are not limited to, those described in Wagh, et al., "Polymers used in ocular dosage form and drug delivery systems", Asian J. Pharm., pages 12-17 (Jan. 2008), which is incorporated herein by reference in its entirety.
  • the insert comprises a polymer selected from polyvinylpyrrolidone (PVP), an acrylate or methacrylate polymer or copolymer (e.g., Eudragit® family of polymers from Rohm or Degussa), hydroxymethyl cellulose, polyacrylic acid, poly(amidoamine) dendrimers, poly(dimethyl siloxane), polyethylene oxide, poly(lactide-co- glycolide), poly(2-hydroxyethylmethacrylate), poly(vinyl alcohol), or poly(propylene fumarate).
  • the insert comprises Gelfoam® R.
  • the insert is a polyacrylic acid of 450 kDa-cysteine conjugate.
  • the ophthalmic composition is a ophthalmic film.
  • Polymers suitable for such films include, but are not limited to, those described in Wagh, et al. (ibid),
  • the film is a soft-contact lens, such as ones made from copolymers of N,N- diethylacrylamide and methacrylic acid crosslinked with ethyleneglycol dimethacrylate.
  • the ophthalmic compositon comprises microspheres or nanoparticles.
  • the microspheres comprise gelatin.
  • the microspheres are injected to the posterior segment of the eye, in the chroroidal space, in the sclera, intravitreally or sub-retinally.
  • the microspheres or nanoparticles comprises a polymer including, but not limited to, those described in Wagh, et al. (ibid), which is incorporated herein by reference in its entirety.
  • the polymer is chitosan, a polycarboxylic acid such as polyacrylic acid, albumin particles, hyaluronic acid esters, polyitaconic acid, poly(butyl)cyanoacrylate, polycaprolactone, poly(isobutyl)caprolactone, poly(lactic acid-co-glycolic acid), or poly(lactic acid).
  • the microspheres or nanoparticles comprise solid lipid particles.
  • the ophthalmic composition comprises an ion-exchange resin.
  • the ion-exchange resin is an inorganic zeolite or synthetic organic resin.
  • the ion-exchange resin includes, but is not limited to, those described in Wagh, et al. (ibid), which is incorporated herein by reference in its entirety.
  • the ion-exhange resin is a partially neutralized polyacrylic acid.
  • the ophthalmic composition is an aqueous polymeric suspension.
  • the therapeutic agent or a polymeric suspending agent is suspended in an aqueous medium.
  • the aqueous polymeric suspensions may be formulated so that they retain the same or substantially the same viscosity in the eye that they had prior to administration to the eye. In some embodiments, they may be formulated so that there is increased gelation upon contact with tear fluid.
  • the present invention includes JAK assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An "isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 C1, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 1, 125 I and 131 I.
  • radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro JAK labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1, 131 1, 35 S or will generally be most useful. For radio-imaging applications U C, 18 F, 125 I, 123 I, 124 I, 131 1, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected
  • the compound incorporates 1, 2, or 3 deuterium atoms.
  • the present invention can further include synthetic methods for incorporating radio- isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.
  • a newly synthesized or identified compound i.e., test compound
  • a test compound which is labeled
  • a test compound can be evaluated for its ability to reduce binding of another compound which is known to bind to a JAK (i.e., standard compound).
  • standard compound the ability of a test compound to compete with the standard compound for binding to the JAK directly correlates to its binding affinity.
  • the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • kits useful for example, in the treatment or prevention of JAK-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • NNN-Tributylbutan- 1 -aminium nitrate from Aldrich, 9.1 g, 30 mmol
  • methylene chloride 100 mL
  • Trifluoroacetic anhydride 4.5 mL, 32 mmol
  • the resulting mixture was then stirred at -5 °C for 30 min and at room temperature overnight.
  • the reaction mixture was concentrated, diluted with ether, filtered.
  • Step I ⁇ trans-4-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl ⁇ methanol
  • Step 4 cis-4- ⁇ 2-[(lR)-l-Hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l- yljcyclohexanecarbonitrile
  • the Boc protected intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.2 mL) at room temperature for 1 h.
  • the mixture was concentrated and purified on RP-HPLC (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give two desired products.
  • First peak retention time 0.253 min.
  • LCMS calculated for C 15 H 18 FN 4 OS (M+H) + : m/z 321.1 ; Found: 321.1.
  • Second peak retention time 0.514 min.
  • LCMS calculated for Ci 5 H 18 FN 4 OS (M+H) + : m/z 321.1 ; Found: 321.1.
  • Step 3 ⁇ trans-4-[( 6-Nitrothieno[3, 2-bJpyridin- 7-yl)amino ] cyclohexyljacetonitrile
  • 7-chloro-6-nitrothieno[3,2-b]pyridine (0.88 g, 4.1 mmol) in isopropyl alcohol (14 mL)
  • (?ra «s-4-aminocyclohexyl)acetonitrile TFA salt (0.68 g, 4.9 mmol)
  • NN-diisopropylethylamine (3.0 mL, 17 mmol
  • Step 4 S-( ⁇ trans-4-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl ⁇ methyl) ethanethioate
  • Step 7 1 - ⁇ trans-4-[(6-Aminothieno [3,2-b] 'pyridin-7-yl) amino] ' cyclohexyl ⁇ -N- methylmethanesulfonamide
  • Step 8 l-(trans-4- ⁇ 2-[(lR)-l-hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l- yl ⁇ cyclohexyl)-N-methylmethanesulfonamide
  • Triethylamine (2.2 mL, 16 mmol), di-tert-butyldicarbonate (2.65 g, 12.1 mmol) and 4- dimethylaminopyridine (0.096 g, 0.79 mmol) were added sequentially to a solution of methanesulfonamide (0.75 g, 7.9 mmol) in methylene chloride (20 mL) at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated. EtOAc was added, and the resultant mixture was washed with IN aq. HC1 solution, dried over MgS0 4 and concentrated to give the desired product (1 g) to be used in the next step directly.
  • Step 1 tert-Butyl (4S)-2,2-dimethyl-4-vinyl-l,3-oxazolidine-3-carboxylate To a suspension of methyl triphenylphosphonium bromide (5.63 g, 15.8 mmol) in tetrahydrofuran (140 mL) was added 2.5 M n-butyllithium in hexane (7.35 mL, 18.4 mmol). The deep red solution was stirred at 0 °C for 1 h.
  • reaction mixture was purged with N 2 three times, and then methylene chloride (21.3 mL), and 1.0 M triethylborane in THF (130 0.13 mmol) was added sequentially. After stirring for 10 min, 2-vinyloxirane (0.150 g, 2.14 mmol) was added and the resulting mixture was stirred overnight. The reaction was diluted with dichloromethane and sat. NaHC0 3 solution. The organic layer was separated and dried over
  • Step 7 ⁇ (5S)-5-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]-5, 6-dihydro-2H-pyran-2-yl ⁇ methyl acetate
  • Step 8 ⁇ (5S)-5-[(6-Aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl ⁇ methyl acetate
  • Step 1 ((2R, 5S)-5- ⁇ 2-[(lR)-l-Hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l- yl ⁇ tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate and ((2S,5S)-5- ⁇ 2-[(lR)-l- hydroxyethyl]-lH-imidazo[4,5-d]thieno[i,2-b]pyridin-l-yl ⁇ tetrahydro-2H-pyran-2-yl)m 4- methylbenzenesulfonate
  • reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give two peaks.
  • prep-LCMS XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min
  • Example 20a ((2R,5S)-5- ⁇ 2-[(lR)-l-Hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin- l-yl ⁇ tetrahydro-2H-pyran-2-yl)acetonitrile hydrate
  • Results showed that the asymmetric unit contains one molecule and one water as shown with thermal ellipsoids drawn to the 50% probability level.
  • the stereochemistry at each of three stereocenters was confirmed.
  • Step 2 bicyclo[2.2. l]heptan-2-amine (from Aldrich, 0.050 g, 0.45 mmol) and triethylamine

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Abstract

Cette invention concerne des dérivés de thiophène condensés tricycliques ; des compositions les contenant et leurs procédés d'utilisation pour moduler l'activité de la Janus kinase (JAK), lesdits dérivés et compositions étant utiles pour traiter les maladies liées à l'activité de JAK comprenant, par exemple, les troubles inflammatoires, les troubles auto-immuns, le cancer, et autres maladies.
EP13789679.1A 2012-11-01 2013-10-31 Dérivés de thiophène condensés tricycliques à titre d'inhibiteurs de jak Withdrawn EP2917221A1 (fr)

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US20160015695A1 (en) 2016-01-21
PH12015500963A1 (en) 2015-08-17
PE20151141A1 (es) 2015-08-06
TWI646099B (zh) 2019-01-01
SG11201503141TA (en) 2015-06-29
US9908895B2 (en) 2018-03-06
HK1214823A1 (zh) 2016-08-05
AR093308A1 (es) 2015-05-27
US10370387B2 (en) 2019-08-06
US11161855B2 (en) 2021-11-02
US11851442B2 (en) 2023-12-26

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